Zhengqiang Wang, PhD

Associate Professor, Center for Drug Design (CDD)

Zhengqiang Wang

Contact Info

wangx472@umn.edu

Office Phone 612-626-7025

Fax 612-625-8154

Office Address:
7-215 Phillips Wangensteen
516 Delaware Street SE
Minneapolis, MN 55455

Mailing Address:
MMC 204
312 Church St. SE
Minneapolis, MN 55455

Associate Professor, Center for Drug Design (CDD)

Program Director for Chemistry, Center for Drug Design (CDD)


PhD, Wayne State University, 2003

Peking University, 1996

Nankai University, 1993

Summary

Expertise

Organic synthesis, computer-aided inhibitor design, assay development and compound screening, chemical probes design and synthesis, in vitro ADME and animal PK.

Research

Research Summary/Interests

Research in my group concerns primarily the design and synthesis of small organic molecules to probe / inhibit protein functions. We are particularly interested in protein targets implicated in the replication of various viruses as well as cellular DNA repair pathways. Our efforts are typically aligned with early drug discovery events, including target validation, lead generation, optimization and characterization, and pharmacokinetics (PK). Currently projects fall into these areas:

Human Immunodeficiency Virus (HIV)
Clinical management of HIV / AIDS relies solely on successful Highly Active Anti-Retroviral Therapy (HAART). Antivirals with novel mechanism of action and / or novel resistance profile are key to sustainable HAART. Toward these ends, we are currently exploring two distinct approaches:

  1. Targeting HIV reverse transcriptase associated RNase H (grant support: NIAID R01AI100890). As a sub-domain of reverse transcriptase (RT), RNase H remains the only HIV encoded enzymatic function yet to be targeted by any known antiviral drugs (Figure 1). While many compounds have been reported to inhibit HIV RNase H biochemically, few were found to inhibit HIV in cell culture and none is known to confer antiviral phenotype via RNase H inhibition. We are conducting major medicinal chemistry efforts aligned toward validating RNase H as an antiviral target against HIV. 

  2. Designing capsid-targeting antivirals (grant support: NIAID R01AI120860). The HIV-1 capsid protein (CA) plays critical roles in multiple steps of the viral replication cycle, including uncoating, reverse transcription, nuclear entry, sites of integration, and assembly. These critical functions are regulated through CA interactions and core stability. Small molecules can increase or decrease the core stability by disrupting CA interactions, and hence confer antiviral phenotypes in a unique way. Our current medicinal chemistry focuses on the design and synthesis of peptidomimetics for probing the structure and functions of HIV CA. 

Hepatitis B Virus (HBV) (grant support: NIAID R01AI121315)
HBV chronically infects 350 million people. Current HBV drugs all target reverse transcription and do not impact the covalently closed-circular DNA (cccDNA), the reservoir for viral persistence. Achieving HBV eradication and disease cure would require the elimination of cccDNA. One way to impact viral ccDNA would be to disrupt the assembly of capsid which is crucial to cccDNA maintenance. We are currently working on identifying small molecule capsid assembly effectors (CAEs). In addition, we are also exploring the impact of inhibiting cellular DNA repair enzyme TDP2 on the formation of viral cccDNA from relaxed circular DNA (RC-DNA).  

Human Cytomegalovirus (HCMV) UL89 (Grant support: UMN CDD Seed and Research Development Grant)

HCMV infection poses a major health threat to immunocompromised individuals such as newborns, HIV and transplant patients. Current drugs all target viral polymerase and suffer from poor efficacy, toxicity and resistance. Hence, there is a pressing need for antivirals with a novel mechanism of action. We are currently targeting the C-terminal endonuclease function of the viral protein UL89 which is important for proper genomic DNA packaging and virus assembly. 

Tyrosyl DNA phosphodiesterase II (TDP2) (grant support: AHC AFRD) TDP2 is a newly discovered DNA repair enzyme and the only known human enzyme capable of cleaving 5’-tyrosyl DNA adducts. It is implicated in the chemotherapeutic resistance of topoisomerase 2 (Top2) poisons, as well as the genome replication of hepadnaviruses (e.g. HBV) and picornaviruses. Inhibiting TDP2 provides pathways toward Top2 poison sensitization in cancer therapy and host-targeting antivirals. We are currently pursuing medicinal chemistry for potent and selective TDP2 inhibitors targeting its active site. 

Research Funding Grants

Current Grant Support (06/2016)

(1) 5R01AI121315 (Multiple PI R01, NIAID / National Institute of Health)
“Taking aim at HBV eradication using novel NRTIs and capsid effectors” 
The goal of this grant is to characterize the structural determinants of HIV capsid (CA) core stability, to unravel structural interactions of CA with host factors and to discover CA-targeting antivirals.
PIs: Stefan Sarafianos,PhD and Zhengqiang Wang,PhD
Grant Period: 06/14/2016—06/13/2021
Direct cost for ZW: $160,000 / Year

(2) 5R01AI120860 (Multiple PI R01, NIAID / National Institute of Health)
“Structural studies of HIV Capsid with host factors and Capsid-targeting antivirals”.
The goal of this grant is to discover and characterize potent capsid effectors and study their antiviral effect in combination with NRTIs
PIs: Stefan Sarafianos,PhD and Zhengqiang Wang,PhD
Grant Period: 06/15/2015-05/31/2020
Direct cost for ZW: $100,000 / Year

(3) 5R01AI100890 (Multiple PI R01, NIAID / National Institute of Health)
“Novel Antivirals Targeting the RNase H Activity of HIV Reverse Transcriptase”.
The goal of this grant is to identify and optimize selective inhibitors of HIV RNase H and study detailed biochemistry of different modes of RNase H activities as well as inhibitor binding sites, and eventually validate RNase H as an antiviral target for HIV chemotherapy.
PIs: Stefan Sarafianos,PhD and Zhengqiang Wang,PhD
Grant Period: 07/01/2012—06/30/2017
Direct cost for ZW: $148,000 / year

(4) University of Minnesota AHC Faculty Research Development Grant
“Structure-Based Discovery of Tyrosyl DNA Phosphodiesterase 2 (TDP2) Inhibitors”
The goal of this grant is to identify inhibitor types and elucidate the mechanism of inhibition of TDP2 through a structure-based approach.
PIs: Hideki Amhara,PhD and Zhengqiang Wang,PhD
Grant Period: 07/01/2014—06/30/2016
Direct cost: $100,000 / year

Patents

  • Wang, Z.; Wu, B.; Kankanala, J.; Tang, J. 3-Hydroxypyrimidine-2,4-dione-5-carboxamides as potent inhibitors of HIV. US Patent Application No. 62127373, 2015
  • Pommier, Y.; Marchand, C.; Wang, Z.; Sirivolu, V. R. (University of Minnesota, USA). Preparation of thioxothiazolidinone derivatives useful as inhibitors of Tdp1. WO 2013055771 A1, 2013.
  • Wang, Z.; Geraghty, R. J.; Vince, R.; Tang, J. (University of Minnesota, USA). N-Hydroxypyrimidine-2,4-diones as inhibitors of HIV and HCV and their preparation. WO2012047993A2, 2012.

Publications

  • Tang, J.; Vernekar, S. K. V.; Chen, Y.-L.; Miller, L.; Huber, A. D.; Myshakina, N.; Sarafianos, S. G.; Parniak, M. P.; Wang, Z.* "Synthesis, Biological Evaluation and Molecular Modeling of 2-Hydroxyisoquinoline-1,3-dione Analogues as Inhibitors of HIV Reverse Transcriptase Associated Ribonulease H and Polymerase" Eur. J. Med. Chem. 2017, doi:10.1016/j.ejmech.2017.03.059
  • Huber, A. D.; Michailidis, E.; Tang, J.; Puray-Chavez, M.; Boftsi, M.; Wolf, J.; Boschert, K.; Sheridan, M.; Leslie, M.; Kirby, K. A.; Singh, K.; Mitsuya, H.; Parniak, M. A.; Wang, Z.; Sarafianos, S. G. "3-hydroxypyrimidine-2,4-diones as novel hepatitis B virus antivirals targeting the viral ribonuclease H" Antimicrob. Agents Chemother. 2017, doi:10.1128/AAC.00245-17.
  • Tang, J.; Kirby, K. A.; Huber, A. D.; Casey, M. C.; Ji, J.; Wilson, D. J.; Sarafianos, S. G.; Wang, Z.* "6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an Inhibitor Scaffold of HIV Reverse Transcriptase: Impacts of the 3-OH on Inhibiting RNase H and Polymerase" Eur. J. Med. Chem. 2017, 128, 168-179.
  •  Wang, Y.; Mao, L.; Kankanala, J.; Wang, Z.; Geraghty, R. J. "Inhibition of Human Cytomegalovirus pUL89 Terminase Subunit Blocks Virus Replication and Genome Cleavage " J. virol. 2016, doi:10.1128/JVI.02152-16.
  • Wu, B.; Tang, J.; Wilson, D. J.; Huber, A. D.; Casey, M. C.; Ji, J.; Kankanala, J.; Xie, J.; Sarafianos, S. G.; Wang, Z.* "3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides potently inhibit HIV-1 integrase and RNase H " J. Med. Chem. 2016. DOI: 10.1021/acs.jmedchem.6b00040
  •  Kankanala, J.; Liu, F.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z.* "Design, Synthesis and Biological Evaluations of Hydroxypyridone Carboxylic Acids as Inhibitors of HIV Reverse Transcriptase-Associated RNase H " J. Med. Chem. 2016, 59, 5051-5062.
  •  Marchand, C.; Abdelmalak, M.; Fesen, K.; Kankanala, J.; Aihara, H.; Wang, Z.; Pommier, Y. “Deazaflavin inhibitors of tyrosyl phosphodiesterase 2 (TDP2) specific for the human enzyme and active against cellular TDP2” ACS Chem. Biol. 2016. DOI: 10.1021/acschembio.5b01047.
  •  Tang, J.; Liu, F.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Wu, B.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z.* "2-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations " J. Med. Chem. 2016, 59, 2648-2659.
  •  Kankanala, J.; Marchand, C.; Abdelmalak, M.; Aihara, H.; Pommier, Y.; Wang, Z.* "Isoquinoline-1,3-diones as Selective Inhibitors of Tyrosyl DNA Phosphodiesterase II (TDP2)" J. Med. Chem. 2016, 59, 2734-2746.
  • Vernekar, S. K. V.; Qiu, L.; Zhang, J.; Kankanala, J.; Li, H.; Geraghty, R. J.; Wang, Z.* “5'-Silylated 3'-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus” J. Med. Chem. 2015, 58, 4016-4028. (Abstract
  • Vernekar, S. K. V.; Liu, Z.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z.* “Design, Synthesis, Biochemical, and Antiviral Evaluations of C6 Benzyl and C6 Biarylmethyl Substituted 2-Hydroxylisoquinoline-1,3-diones: Dual Inhibition against HIV Reverse Transcriptase-Associated RNase H and Polymerase with Antiviral Activities” J. Med. Chem. 2015, 58, 651-664.
  • Vernekar, S. K. V.; Qiu, L.; Zacharias, J.; Geraghty, R. J.; Wang, Z.* “Synthesis and Antiviral Evaluation of 4’-(1,2,3-Triazol-1-yl) thymidines” Med. Chem. Commun. 2014, 5, 603-608.
  •  Sirivolu, V. R.; Vernekar, S. K. V.; Ilina, T.; Myshakina, N. S.; Parniak, M. A.; Wang, Z.* "Clicking 3’-Azidothymidine into Novel Potent Inhibitors of Human Immunodeficiency Virus" J. Med. Chem. 2013, 56, 8765–8780. Abstract
    AHCCDD2-Image-ZWang-TOCGraphic1_Border
  • Sirivolu, V. R; Vernekar, S. V; Marchand, C; Naumova, A; Chergui, A; Renaud, A; Stephen, A; Chen, F; Sham, Y. Y; Pommier, Y; Wang, Z.* “5-Arylidenethioxothiazolidinones as Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp1)” J. Med. Chem. 2012, 55, 8671-8684. Abstract.
  • Chen, Y.-L.; Zacharias, J.; Vince, R.; Geraghty, R. J.; Wang, Z.* "C-6 Aryl Substituted 4-Quinolone-3-carboxylic Acids as Inhibitors of Hepatitis C Virus" Bioorg. Med. Chem. 2012, 20, 4790-4800.Abstract
    AHCCDD2-Image-ZWang-TOCGraphic2_Border
  • Kirby, K.; Marchand, B.; Ong, Y.; Adongwe, T.; Hachiya, A.; Michailidis, E.; Leslie, M.; Sietsema, D.; Fetterly, T.; Dorst, C.; Singh, K.; Wang, Z.; Parniak, M.; Sarafianos, S. "Structural and Inhibition Studies of the RNase H Function of Xenotropic Murine Leukemia Virus-Related Virus Reverse Transcriptase" Antimicrob. Agents Chemother. 2012, 56, 2048-2061. Abstract
  • Chen, Y.-L.; Tang, J.; Kesler, M. J.; Sham, Y. Y; Vince, R.; Geraghty, R. J.; Wang, Z.* "The Design, Synthesis and Biological Evaluations of C-6 or C-7 Substituted 2-Hydroxyisoquinoline-1,3-diones as Inhibitors of Hepatitis C Virus" Bioorg. Med. Chem. 2012, 20, 467-479. Abstract
    AHCCDD2-Image-ShamTOCGraphic2_Border
  • Tang, J.; Maddali, K.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z.* “3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase” J. Med. Chem. 2011, 54, 2282-2292. Abstract
  • Tang, J.; Maddali, K.; Dreis, C. D.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z.* “6-Benzoyl-3-hydroxypyrimidine-2,4-diones as Dual Inhibitors of HIV Reverse Transcriptase and Integrase” Bioorg. Med. Chem. Lett. 2011, 21, 2400-2402. Abstract
  • Tang, J.; Maddali, K.; Dreis, C. D.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z.* “N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase” ACS Med. Chem. Lett. 2011, 2, 63-67. Abstract
  • Tang, J.; Maddali, K.; Pommier, Y.; Sham, Y. Y.; Wang, Z.* “Scaffold rearrangement of dihydroxypyrimidine inhibitors of HIV integrase: Docking model revisited” Bioorg. Med. Chem. Lett.2010, 20, 3275-3279. Abstract
  • Wang, Z.*; Tang, J.; Salomon, E. C.; Dreis, C. D.; Vince, R. “Pharmacophore and Structure-Activity-Relationship on Integrase Inhibition within a Dual Inhibitor Scaffold of HIV Reverse Transcriptase and Integrase” Bioorg. Med. Chem. 2010, 18, 4202-4211. Abstract
  • Wang, Z.*; Vince, R. " Design and synthesis of dual inhibitors of HIV reverse transcriptase and integrase: Introducing a diketoacid functionality into delavirdine" Bioorg. Med. Chem. 2008, 16, 3587-3595. Abstract
  • Wang, Z.*; Vince, R. “Synthesis of Pyrimidine and Quinolone Conjugates as a Scaffold for Dual Inhibitors of HIV Reverse Transcriptase and Integrase” Bioorg. Med. Chem. Lett. 2008, 18, 1293-1296. Abstract
  • Wang, Z.; Bennett, E. M; Wilson, D. J.; Salomon, C.; Vince, R. “Rationally Designed Dual Inhibitors of HIV Reverse Transcriptase and Integrase”. J. Med. Chem. 2007, 50, 3416. Abstract